chr14-64295199-A-AC

Variant names:

• chr14-64295199-A-AC
• rs3841304
• ENST00000554572.5:c.-91+2333_-91+2334insG

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1 BS2

The ENST00000554572.5(ESR2):​c.-91+2333_-91+2334insG variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00348 in 146,306 control chromosomes in the GnomAD database, including 3 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.0035 (3 hom., cov: 30)
• Consequence: ESR2 ENST00000554572.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.117
• Publications: 1 publications found

Genes affected

ESR2 (HGNC:3468): (estrogen receptor 2) This gene encodes a member of the family of estrogen receptors and superfamily of nuclear receptor transcription factors. The gene product contains an N-terminal DNA binding domain and C-terminal ligand binding domain and is localized to the nucleus, cytoplasm, and mitochondria. Upon binding to 17beta-estradiol or related ligands, the encoded protein forms homo- or hetero-dimers that interact with specific DNA sequences to activate transcription. Some isoforms dominantly inhibit the activity of other estrogen receptor family members. Several alternatively spliced transcript variants of this gene have been described, but the full-length nature of some of these variants has not been fully characterized. [provided by RefSeq, Jul 2008]

ESR2 Gene-Disease associations (from GenCC):

• male infertility with azoospermia or oligozoospermia due to single gene mutation

  Inheritance: AR Classification: MODERATE Submitted by: King Faisal Specialist Hospital and Research Center
• familial medullary thyroid carcinoma

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• ovarian dysgenesis 8

  Inheritance: AD, Unknown Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00348 (509/146306) while in subpopulation SAS AF = 0.0288 (134/4656). AF 95% confidence interval is 0.0248. There are 3 homozygotes in GnomAd4. There are 281 alleles in the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 AD,AR,Unknown gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ESR2	NM_001291712.2	c.-91+2333dupG		intron_variant	Intron 6 of 13		NP_001278641.1
ESR2	NM_001291723.1	c.-90-12125dupG		intron_variant	Intron 1 of 8		NP_001278652.1
ESR2	NR_073496.2	n.717-12125dupG		intron_variant	Intron 1 of 7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ESR2	ENST00000554572.5	c.-91+2333_-91+2334insG		intron_variant	Intron 6 of 13	1		ENSP00000450699.1
ESR2	ENST00000358599.9	c.-90-12125_-90-12124insG		intron_variant	Intron 1 of 8	2		ENSP00000351412.5

Frequencies

GnomAD3 genomes AF: 0.00348 AC: 509 AN: 146192 Hom.: 3 Cov.: 30

Gnomad AFR AF: 0.00164

Gnomad AMI AF: 0.0242

Gnomad AMR AF: 0.00323

Gnomad ASJ AF: 0.000300

Gnomad EAS AF: 0.000586

Gnomad SAS AF: 0.0285

Gnomad FIN AF: 0.000289

Gnomad MID AF: 0.0331

Gnomad NFE AF: 0.00329

Gnomad OTH AF: 0.00456

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.00348 AC: 509 AN: 146306 Hom.: 3 Cov.: 30 AF XY: 0.00393 AC XY: 281 AN XY: 71582

African (AFR) AF: 0.00166 AC: 64 AN: 38536

American (AMR) AF: 0.00323 AC: 48 AN: 14868

Ashkenazi Jewish (ASJ) AF: 0.000300 AC: 1 AN: 3328

East Asian (EAS) AF: 0.000587 AC: 3 AN: 5108

South Asian (SAS) AF: 0.0288 AC: 134 AN: 4656

European-Finnish (FIN) AF: 0.000289 AC: 3 AN: 10392

Middle Eastern (MID) AF: 0.0284 AC: 8 AN: 282

European-Non Finnish (NFE) AF: 0.00329 AC: 218 AN: 66274

Other (OTH) AF: 0.00451 AC: 9 AN: 1996

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00249

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.12
Mutation Taster		=100/0	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs3841304; hg19: chr14-64761917;